1. Field of the Invention
This invention relates to an improved process for the production of penicillanic acid compounds which are useful as intermediates in the synthesis of penicillin series of antimicrobial agents.
2. Description of the Prior Art
Penicillanic acid 1,1-dioxide (sulbactam) is known as an useful .beta.-lactamase inhibitor. A mutual prodrug derived from said sulbactam and ampicillin, namely 1,1-dioxopenicillanoyloxymethyl 6-[D-(2-amino-2-phenylacetylamino)]penicillanate (sultamicillin) is a drug developed for increasing the blood and tissue concentrations of ampicillin and sulbactam and for attaining synergism therebetween in .beta.-lactamase resistance. Japanese Kokai Tokkyo Koho JP No. 59-98090 or U.S. Pat. No. 4,530,792 discloses 1,1-dioxopenicillanoyloxymethyl 6-(2-phenyl or phenoxy-acetylamino)penicillanate (hereinafter referred to as "compound A") and a method of producing sultamicillin from said compound A. The method disclosed for producing compound A comprises either reacting a salt of 6-(2-phenylacetylamino)penicillanic acid (penicillin G) or 6-(2-phenoxyacetylamino)penicillanic acid (penicillin V) with chloromethyl phenicillanate 1,1-dioxide (chloromethyl ester of sulbactam) or reacting a salt of sulbactam with chloromethyl 6-(2-phenylacetylamino)penicillanate (chloromethyl ester of penicillin G) or chloromethyl 6-(2-phenoxyacetylamino)penicillanate (chloromethyl ester of penicillin V). Such chloromethyl ester compounds are particularly important intermediates in the synthesis of diester compounds.
A number of references may be cited concerning the production of such chloromethyl ester compounds. Thus, for instance, Swiss Patent No. 645,902 discloses a method of chloromethyl esterification which comprises reacting sulbactam with chloroiodomethane in an appropriate solvent. Further, the above U.S. Pat. No. 4,530,792 or Japanese Kokai Tokkyo Koho JP No. 59-98090 discloses a method of producing such chloromethyl ester compounds which comprises reacting sulbactam, penicillin G or penicillin V with tetrabutylammonium hydroxide and then reacting the resulting tetramethylammonium salt with chloroiodomethane.
The above-mentioned known reactions for producing said chloromethyl ester compounds generally give low yields and require column separation for purification, hence are not fully satisfactory from the industrial viewpoint. Furthermore, the chloromethylating agent used there, namely chloroiodomethane, is a very expensive. It is difficult to obtain said compound commercially at low cost. A process is also known which comprises, for increasing the reactivity of sulbactam, penicillin G or penicillin V, reacting the same with a sufficient amount of tetrabutylammonium hydroxide, tetrabutylammonium chloride or the like to convert the same to the corresponding tetrabutylammonium salt and then reacting said salt with an excessive amount of chloroiodomethane under anhydrous conditions. However, this process has various problems: for instance, it involves two reaction steps, the operation is troublesome, the yield is low and, as for the reaction period, it is sometimes necessary to carry out the reaction overnight with stirring.
Further U.S. Pat. No. 4,704,456 discloses that a process for the preparation of chloromethyl ester of sulbactam which comprises reacting the tetrabutylammonium salt of sulbactam with a molar excess of bromochloromethane or chloroiodomethane in a solvent comprising said molar excess of bromochloromethane or chloroiodomethane in the presence of 0.1 to 1.0 molar equivalents of a beta-diketone or a tertiary amine. The process is troublesome from the industrial viewpoint since the tetrabutylammonium salt of sulbactam has to be isolated and reacted with bromochloromethane or chloroiodomethane in the dark.